Estimating the "steric clash" at cis peptide bonds

Area of Science:

• Biochemistry
• Computational Chemistry
• Structural Biology

Background:

• Cis peptide bonds are infrequent in proteins, particularly for non-proline residues.
• Steric clashes between side chains are often cited as the reason for this scarcity.
• The energy cost associated with these steric conflicts requires precise quantification.

Purpose of the Study:

• To estimate the energy cost of steric clashes in protein backbones that lead to cis peptide bond formation.
• To model the interactions between amino acid side chains using computational chemistry.
• To establish a baseline energy penalty for all-cis peptide chains.

Main Methods:

• Utilized quantum chemistry approaches, including differential-torsion protocols.
• Employed bond-separation-energy analyses on model compounds like N-ethyl propionamide.
• Calculated C beta...C beta interactions analogous to alanine dipeptides.

Main Results:

• The study found an energy increment of approximately 9 kcal/mol for methyl-methyl contacts, similar to n-hexane rotamers.
• Larger side chains (leucine, phenylalanine) did not significantly alter this energy increment.
• Explicit modeling demonstrated that the steric penalty can be reduced by a factor of up to 4.

Conclusions:

• The calculated 9 kcal/mol energy increment provides a reference value for the energetic barrier to forming all-cis peptide chains.
• Local side chain interactions, like methyl-methyl contacts, significantly contribute to the cis peptide bond scarcity.
• Protein structural modeling can mitigate these steric penalties, reducing the energetic cost.